An excitatory synapse hypothesis of depression

Abstract

Depression is a common cause of mortality and morbidity, but the biological bases of the deficits in emotional and cognitive processing remain incompletely understood. Current antidepressant therapies are effective in only some patients and act slowly. We propose an excitatory synapse hypothesis of depression in which chronic stress and genetic susceptibility cause changes in the strength of subsets of glutamatergic synapses at multiple locations, including the prefrontal cortex, hippocampus and nucleus accumbens, leading to a dysfunction of cortico-mesolimbic reward circuitry that underlies many of the symptoms of depression. This hypothesis accounts for current depression treatments and suggests an updated framework for the development of better therapeutic compounds.

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

“…[9][10][11][12][13]90 A possible change in AMPAR and NMDAR functions in mediating the antidepressant effect of ketamine is supported by a study using magnetic resonance spectroscopy in healthy human controls showing an increased glutamine/glutamate ratio induced by ketamine after 24 h, reflecting increased synaptic glutamate neurotransmission, specifically in frontal cortical regions with high density of AMPARs. 91 Our present data, which demonstrate a reduced synaptic potentiation and AMPAR function in VTA-NAc circuit, may therefore appear contradictory.…”

“…Several lines of evidence suggest that depression is associated with altered synaptic plasticity of excitatory synapses and that ketamine promotes AMPAR function and synaptogenesis. [9][10][11][12][13] Thus, modulation of glutamatergic neurotransmission and plasticity in the hippocampus and medial prefrontal cortex is suggested to mediate the antidepressant action of ketamine. [9][10][11][12][13] Both AMPARs and NMDARs are critical elements of forms of long-term synaptic plasticity such as longterm potentiation (LTP), a potential neurophysiological correlate of learning and memory.…”

Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior

“…We further detected increased sEPSC amplitude in the Ndrg2 -/-CA1 pyramidal neurons, suggesting that elevated interstitial glutamate levels underlie the enhanced excitation. Excitatory glutamatergic system dysfunction plays an important role in the pathogenesis of neuropsychiatric disorders (58)(59)(60)(61)(62). A few studies have investigated the role of glutamate in the context of ADHD (63,64), although their conclusions are not completely consistent.…”

Molecular, Functional, and Structural Imaging of Major Depressive Disorder

“…Thus, the specificity of the changes remain an issue. In addition, besides involvement of the serotonergic system, abnormal neurotrophin signaling [4], aberrant expression of inflammatory cytokines [126,127], and the dopaminergic system [128][129][130] are thought to contribute to the genesis of depression as well. Therefore, the occurrence and development of the disorder is a complex process involving multiple mechanisms.…”

“…According to the latest report, MDD has been ranked as the second medical condition with the greatest disease burden worldwide based on years lived with disability [3]. MDD is associated with numerous negative consequences, including health and social issues, among which suicide is the most devastating consequence attempted by as many as 8% of severe MDD patients [4]. Strikingly, only *50% of MDD patients respond to standard-of-care antidepressants [5], with *70% failing to achieve complete remission [6].…”